The cause of stroke in women is frequently unknown, despite recognition of cardiovascular risk factors and appropriate prevention treatment. The reason may be related to unrecognized subclinical disease, which may be manifested by ongoing thrombin generation, inflammation, endothelial dysfunction, and abnormal responses to vascular stresses. In addition, endogenous hormones such as estradiol and sex hormone binding globulin, as well as menopausal status impact cardiovascular risk. The aims of this K02 project are to: 1) Identify biological and physiological markers associated with ischemic stroke in women, and 2) Establish which biological and physiological markers are influenced by sex hormones and/or menopausal status in women with stroke. The working hypotheses are that women with ischemic stroke will have evidence of ongoing inflammation, thrombin generation, endothelial dysfunction, quantified by functional responses to forearm ischemia and measures of arterial stiffness, low sex hormone binding globulin, or a combination of the above processes. Using a case-control cohort design, 75 women with an ischemic stroke and 75 without ischemic stroke matched by age 2 years, menopausal status, and cardiovascular risk factors will be enrolled. Biological markers include tissue factor, matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule-1 (VCAM-1), von Willebrand Factor (vWF), and thrombin-antithrombin III complex (TAT). Vascular studies include brachial artery flow-mediated dilation (measure of endothelial response to ischemia), carotid-femoral pulse wave velocity (measure of arterial stiffness), and ankle-brachial index (measure of peripheral vascular disease). Estradiol, testosterone, sex hormone binding globulin, and follicle stimulating hormone (for menopausal status determination) will also be measured. The significance of each marker will be assessed by plotting ROC curves for each marker, and then entering the significant markers into a multivariable model to determine the best combination of markers of stroke. Both groups of women will be followed for a minimum of two years after enrollment for any vascular outcomes, such as stroke, TIA, or acute coronary syndromes. The expected outcomes of this study will be the discovery of novel biological and vascular markers for stroke, and how endogenous sex hormones impact those markers. This could naturally lead to development of a predictive panel of markers for future stroke risk.